Conformational changes in muscarinic receptors may produce diminished cholinergic neurotransmission and memory deficits in aged rats
Conformational changes in muscarinic receptors may produce diminished cholinergic neurotransmission and memory deficits in aged rats
复制标题
毒蕈碱受体的构象变化可能导致老年大鼠胆碱能神经传递减弱和记忆缺陷
DOI：
10.1016/0197-4580(85)90010-7
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发表时间：
1985
影响因子：
4.2
通讯作者：
J. Joseph
中科院分区：
文献类型：
--
作者：
A. Lippa;C. Loullis;J. Rotrosen;D. M. Cordasco;D. Critchett;J. Joseph
临床和实验室研究都表明，与年龄相关的记忆缺陷可能是由于，至少部分是由于毒蕈碱乙酰胆碱（mAChR）受体的干扰。为了进一步验证这一假设，本研究检测了青年、中年和老年动物海马锥体细胞对离子导入ACh的电生理反应率。年龄和海马中的毒蕈碱激动剂和拮抗剂结合之间的关系也进行了研究。此外，通过测定钙调素水平和磷脂甲基转移酶I和II的活性来评估受体-效应器偶联中可能与年龄相关的变化。电生理数据的分析表明，选择性年龄相关的ACh的能力，改变爆发率，但不是简单的穗率递减。这些与年龄相关的ACh增加爆发率的功效的降低并不被mAChR密度的降低所抵消（通过3 H-QNB结合来评估），但它们在时间上被氧震颤素与3 H-QNB结合能力的年龄相关变化所抵消。在幼年动物中，这些分析得出的希尔系数接近1，而在中年和老年动物中，希尔系数显着偏离1，表明可能存在2种或多种对氧震颤素具有不同亲和力的受体状态在2个老年组中。当氨甲酰胆碱被用来取代3 H-QNB，这些复杂的结合模式，甚至在年轻人中看到，因为氨甲酰胆碱诱导mAChR的构象/取向的变化，而oxotremorine不。有人建议，在记忆能力的下降，以前已经报道，平行的年龄相关的构象/取向的变化中观察到的mAChR，因为这些变化的结果在一个受体，是“神经生理脱敏”。
Both clinical and laboratory studies suggest that age-related memory deficits may be due, at least in part, to disturbances in muscarinic acetylcholine (mAChR) receptors. In order to further evaluate this premise, the present studies examined the electrophysiological responses rates of hippocampal pyramidal cells to iontophoretically applied ACh in young, middle-age and aged animals. The relationship between age and muscarinic agonist and antagonist binding in the hippocampus was also examined. In addition, possible age-related changes in receptor-effector coupling were assessed by determining calmodulin levels and the activities of phospholipid methyltransferase I and II. Analysis of electrophysiological data showed selective age-related decrements in the ability of ACh to alter burst rate but not simple spike rate. These age-related decreases in the efficacy of ACh to increase burst rate were not paralleled by decreases in mAChR density as assessed by3H-QNB binding, but they were temporally paralleled by age-related changes in the ability of oxotremorine to inhibit3H-QNB binding. In the young animals, the resultant Hill coefficients derived from these analyses approached 1, while in the middle and old aged animals, the Hill coefficients deviated significantly from 1, indicating the possible existence of 2 or more receptor states with differential affinity for oxotremorine in the 2 older age groups. When carbamylcholine was used to inhibit3H-QNB, these complex binding patterns were seen even in the young, since carbamylcholine induces conformational/orientational changes in the mAChR while oxotremorine does not. It is suggested that declines in mnemonic ability that have been reported previously, parallel the age-related conformation/orientational changes observed in the mAChR since these changes result in a receptor that is “neurophysiologically desensitized.”
脑脊液乙酰胆碱、胆碱与阿尔茨海默氏型老年性痴呆。
影响因子：
--
作者：
Davis,KL;Hsieh,JY;Levy,MI;Horvath,TB;Davis,BM;Mohs,RC
通讯作者：
Mohs,RC